Blood and tissue detoxification method

ABSTRACT

Method and apparatus for blood and tissue detoxification by oxidation of excess undesirable or toxic substances such as ammonia, urea, creatinine, alanine, carbon monoxide, drug overdoses, uric acid, acetone, aceto acetate and ethanol in an electrochemical cell which may be implanted or used in an extracorporeal shunt system. The cell may be hybridized with a battery to drive the cell under certain conditions, and the cell may be employed as part of a blood toxic substance level monitoring system. The invention is typified by the case where electrochemical cells convert oxygen and the enumerated toxic substances in the body fluids to harmless products such as CO2, water and nitrogen which are easily dissipated. The cells have hydrophobic cathodes having a membrane thereover of silicone rubber, polyfluorocarbon, polycarbonate, and copolymers thereof which permit diffusion of oxygen therethrough. The anodes may be either hydrophilic or hydrophobic, the former employing a membrane thereover of cellulose or a cation resin and the latter a silicone rubber toxic substance- diffusible membrane. The electrodes are separated by an anion exchange membrane, or inorganic matrix edge-impregnated with a cation exchange membrane. The cells are simple of construction, and typically thin, wafer-like in form which permits ease of implantation at any desired location in the body. In its broadest aspect, the invention involves the use of electrochemical cells in the manner of artificial organs to remove toxic substances the body is unable to metabolize. Ammonia and ethanol, uric acid, urea, drugs such as digitalis glycosides or barbiturates, and toxic agents such as methanol may be oxidized to nontoxic products such as N2, H2O, acetate and CO2. Diabetic acidosis can be improved by oxidizing ketone bodies and aceto acetate to CO2 and water. This method will detoxify or eliminate any substance which is oxidizable to harmless or less harmful products and which can be selectively or non-selectively admitted to the anode by means of specific or non-specific covering membranes. The anode itself may also be selective with respect to the toxic substance to be eliminated. In specific embodiments, the electrochemical cell can be used in an extracorporeal shunt system to rapidly oxidize dialysate-urea and dialysate-ammonia contained in hemodialysis fluid.

United States Patent 1191 Yao et al.

[ 51 Apr. 22, 1975 1 1 BLOOD AND TISSUE DETOXIFICATION METHOD [76]Inventors: Shang J. Yao, 5 Bayard Rd.. Apt.

920, Pittsburgh, Pa. 15213; Sidney K. Wolfson, 205 Buckingham Rd..Pittsburgh. Pa. 15215 [22] Filed: Apr. 17, I973 [21] Appl. No.: 352,070

Related US. Application Data [63] Continuation-in-part of Scr. No.244,071, April 14,

1972, abandoned.

[52] U.S. CI 3/1; 128/214 R; 204/302; 210/321 [51] Int. Cl. A6lf 1/24[58] Field of Search... 3/1; 128/1 R, 214 R, DIG. 3. 128/419 B; 210/321[56] References Cited UNITED STATES PATENTS 3.353.539 11/1967 Preston128/419 B 3,370,710 2/1968 Blucmlc 210/321 OTHER PUBLICATIONS A SingleElectrolyte Fuel Cell Utilizing Permselective Membranes." by S. K.Wolfson et al.. transactions American Society for Artificial InternalOrgans. Vol. 16, 1970, pages 193-198.

Primary Exmniner-Ronald L. Frinks Attorney. Agent, or Firm-Jacques M.Dulin [57] ABSTRACT tery to drive the cell under certain conditions, andthe cell may be employed as part of a blood toxic substance levelmonitoring system. The invention is typified by the case whereelectrochemical cells convert oxygen and the enumerated toxic substancesin the body fluids to harmless products such as CO water and nitrogenwhich are easily dissipated. The cells have hydrophobic cathodes havinga membrane thereover of silicone rubber, polyfluorocarbon,polycarbonate. and copolymers thereof which permit diffusion of oxygentherethrough. The anodes may be either hydrophilic or hydrophobic, theformer employing a membrane thereover of cellulose or a cation resin andthe latter a silicone rubber toxic substancediffusible membrane. Theelectrodes are separated by an anion exchange membrane, or inorganicmatrix edgeimpregnated with a cation exchange membrane. The cells aresimple of construction, and typically thin. wafer-like in form whichpermits ease of implantation at any desired location in the body. In itsbroadest aspect, the invention involves the use of electrochemical cellsin the manner of artificial organs to remove toxic substances the bodyis unable to metabolize. Ammonia and ethanol. uric acid, urea, drugssuch as digitalis glycosides o'r barbiturates, and toxic agents such asmethanol may be oxidized to nontoxic products such as N H O, acetate andCO Diabetic acidosis can be improved by oxidizing ketone bodies andaceto acetate to CO and water. This method will detoxify or eliminateany substance which is oxidizable to harmless or less harmful productsand which can be selectively or non-selectively admitted to the anode bymeans of specific or non-specific covering membranes. The anode itselfmay also be selective with respect to the toxic substance to beeliminated. In specific embodiments, the electrochemical cell can beused in an extracorporeal shunt system to rapidly oxidize dialysate-ureaand dialysate-ammonia contained in hemodialysis fluid.

19 Claims, 20 Drawing Figures BLOOD AND TISSUE DETOXIFICATION METHODCROSS REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of our copending application, Ser. No. 244,071,filed Apr. 14, 1972, and now abandoned, the teachings of which areincorporated by reference herein.

FIELD This invention relates to method and apparatus for removal oftoxic or unwanted substances such as ammonia, urea and ethanol fromblood, dialysate and body tissue fluids. More specifically, theinvention is directed to electrochemical autooxidation cells such as onewhich employs ambient fluid oxygen levels to oxidize ammonium ions tonontoxic water and N and urea to nontoxic N H and CO removable bynatural homeostatic processes. The cells may be adapted for directimplantation into the patients blood stream or body tissue spaces, or tobe employed in an extracorporeal blood shunt or in combination with adialysate unit. The cells may also be hybridized with a battery oremployed as a monitor of ammonia or other reactant levels.

BACKGROUND Chronic hepatic failure and acute ammonia intoxication areserious diseases involving abnormally high blood-ammonia levels. Acutealcoholic coma obviously results from markedly elevated tissue alcohollevels. Previous methods for treating patients having such diseasesinclude: dietary protein restriction, antibiotic administration.hemodialysis. extracorporeal ionexchange blood\ shunts, and finally,transplantation of donor liver. The blood shunt involves passing bloodthrough an external shunt loaded with micro-capsules containingion-exchange resins which remove the ammonia and replace it with sodiumions. As well as involving aseptic surgical techniques and providingonly periodic relief, the external shunt may lead to high blood sodiumlevels.

Recent developments in methods for urea removal in hemodialysis involvethe action of urease on urea with the release of large quantities ofammonia as a product. The presence of a high ammonia concentration inthe dialysate rapidly leads to reverse dialysis of ammonia and markedincreases in the patients blood ammonia level. To prevent this fromhappening, the released ammonia is then either adsorbed or trapped bymicroencapsulated cation exchange resin [Chang, T.M.S., Semi-permeableAqueous Microcapsules Artificial Cells": With Emphasis on Experiments inan Extracorporeal Shunt System, Trans. Amer. Soc. Artif. lnt. Organs,121l3-l9 l966); Sparks, R. E., Solemme, R. M., Meier. P. M., Litt, M. H.and Lindan, 0., Removal of Waste Metabolites in Uremia byMicroencapsulated Reactants, Trans. Amer. Soc. Artif, lnt. Organs,:353-58 (1969)], or by zirconium phosphate [Gordon, A., Greenbaum, M.A., Marantz, L. B., McArthur, M. and Maxwell. M. H., A sorbent-basedLow-Volume Recirculating Dialysate System, Trans. Amer. Soc. Artif. lnt.Organs, 15:347-52 (I969); Greenbaum, M. A. and Gordon, A., A.Regenerative Dialysis Supply System, Dial. Transpl, 1:18-30 (1972)]. Thezirconium phosphate system also includes activated carbon and zirconiumoxide and urease to convert urea in dialysate to ammonium carbonate.This system was developed by the Marquardt Co. in Van Nuys, California,under the trademark REDY. These systems have the advantage that a smallvolume of water (tap), which is recycled, can replace very large volumesof expensive dialysis fluid. The bulk of equipment is thus also markedlyreduced. The major difficulty of this adsorption or ionexchange methodis that the sorbent becomes saturated.

THE INVENTION Objects It is therefore an object of the present inventionto provide an automatic process for continuous removal of toxicsubstances from blood and tissue of patients having abnormally highlevels of these substances.

It is also an object of this invention to provide an implantable devicewhich operates continuously in the patients body for the patients lifespan.

It is another object of the invention to provide an implantable devicewhich employs electrocatalysts to automatically and continuously reactwith both oxygen and excess toxic substances such as ammonia present inthe body fluids in the case of a hepatic disease patient or of othersubstances such as urea in different disease or toxic states asmentioned above.

It is another object of this invention to provide an implantable deviceto continuously measure the ammonia, urea or other toxic substance levelin the tissues of a patient.

It is another object of this invention to provide a miniaturized hybridsystem comprising an electrochemical cell utilizing the toxic substancein combination either with the toxic substance level measuring device ora battery, or both.

It is another object of this invention to provide an electrochemicalsystem or extracorporeal shunt system for removal of excess toxicsubstances at higher rates than would result from spontaneous reaction.

It is another object of this invention to provide a novel cell of thetype described which is adapted to be implanted in the body ofa patient,and capable of using ambient body fluid oxygen levels for oxidizing thebody toxic substance(s) to nontoxic products.

It is another object of this invention to provide an extracorporealshunt system which rapidly oxidizes toxic substances such as ammonia orurea to harmless nontoxic by-products. such as nitrogen and water whichare removed by homeostatic processes.

It is another object of this invention to provide an extracorporealshunt system which rapidly oxidizes. electrochemically, dialysateammonia generated by the action of urease on urea in hemodialysis toharmless nontoxic nitrogen and water which can be reabsorbed by thepatient and removed by homeostatic processes.

It is another object of this invention to position the electrochemicalcell in a closed dialysis loop after the urease reactor.

It is another object to provide an implantable cell which is in situwith a urease reactor whereby a urease microencapsulated material isactually packed into the blood space between electrodes so that theelectrodes are in contact with a higher concentration of ammonia due tothe close proximity of the urease capsules where ammonia is generated.

It is another object of this invention to provide an extracorporealshunt system which directly and rapidly oxidizes dialysate-urea in renaldialysis to harmless nontoxic carbon dioxide, nitrogen and water. whichare removed by homeostatic processes. This is accomplished without priorconversion of the dialysate-urea to NH by urease.

Still other and further objects of this invention will be evident fromthe detailed description which follows.

THE FIGURES The detailed description has reference to the followingfigures which are meant as illustrative and not limiting. and whichrefer to the specific instance of an ammonia or urea detoxifying cellwhich could also be used equally as well as an ethanol etc. detoxifyingcell in most of its embodiments. With minor modifications in material.it could describe similar systems to detoxify other substances such asuric acid. digitalis. methanol, barbiturates, etc.. as described above.

FIG. 1 is a schematic diagram ofa cell in accordance with this inventionhaving a hydrophobic cathode and hydrophilic anode.

FIG. 2 is a schematic diagram ofa cell in accordance with this inventionhaving a hydrophobic cathode and a hydrophobic anode.

FIG. 3 is an exploded view showing the component parts of a typical cellof this invention.

FIG. 4 is a section view through a typical cell such as in FIG. 3showing the flexibility of such cells and a corrugated construction toincrease surface area.

FIG. 5 shows typical thoracic cavity or subcutaneous locations forimplantation of cells in accordance with this invention.

FIG. 6 shows typical locations for implantation of cells in accordancewith this invention within the abdominal cavity.

FIG. 7 shows in schematic perspective the extracorporeal shunt systememploying a series of cells in accordance with this invention.

FIG. 8 is a schematic electrical diagram of the extracorporeal shuntsystem of this invention showing the power supply and resistors.

FIGS. 9A and 9B illustrate the electrical schematic of the hybrid systemin two modes of operation, that of high toxic substance concentration(FIG. 9A) and that of low toxic substance concentration (FIG. 93).

FIG. 10 illustrates. schematically, an embodiment of this inventionwherein an electrochemical cell assembly is connected to a urease-loadedcartridge. with the dialysate flowing first through the urease cartridgebefore it reaches the electrochemical cell assembly.

FIG. 11 is a schematic diagram illustrating the interior of anelectrochemical cell assembly wherein the anode surfaces are exposed tourease-loaded microcapsules.

FIG. 12 is a detailed. sectional view of a ureaseloaded electrochemicalcell taken along section line l2-l2 of FIG. 11.

FIG. 13 is a schematic diagram of an extracorporeal shunt deureatorsystem wherein a urea selective anode converts urea directly to harmlessproducts.

FIG. 14 illustrates an oscilloscope (cyclic) scan that is obtained asurea is oxidized in a phosphate buffer solution in accordance with thisinvention.

FIG. 15 illustrates the effect of adding urea to an electrochemical celloperating with glucose in a bicarbonate buffer at the anode and air atthe cathode.

FIG. 16 illustrates the effect of adding endogenous substances tosandwich cells of the general type illustrated in FIG. 3.

FIGS. l7, l8 and 19 illustrate the effect of endogenous substances withwhole plasma, plasma dialysate and macromolecule residual from thedialysis of plasma in glucose fuel cells respectively.

SUMMARY The invention comprises providing an electrochemical cell systemin which toxic substances are oxidizable reactants and oxygen air orother reducible constituents such as N0 POE. S0 is an oxidant. Thedescription will particularly relate to the specific situation in whichblood or tissue ammonia or urea is the toxic substance, but theinvention is not restricted to this example. Both the ammonia or ureaand the oxygen are supplied continuously by blood or by tissue fluid.The cell employs electrocatalysts to automatically and continuouslyreact with the oxygen, and excess ammonia in a typical hepatic diseasepatient. or urea in the case of kidney failure. to oxidize the ammoniaor urea to nitrogen, cafbon dioxide and water. These reaction productsare nontoxic and are removed by homeostatic processes natural to thebody. A high level of power output is not essential to the operation ofthe cell system of this invention. The cell permits continuous removalof excess ammonia or urea, which is an important form of therapy in anacute or chronic hepatic or kidney failure. In addition, electroniccontrol, and/or combination with implantable batteries or implantableglucose fuel cell (bioautofuel cell) as referred to in Wolfson. S. K.,.lr., Yao. S. .l.. Geisel. A. and Cash. H. R.. Jr. A Single ElectrolyteFuel Cell Utilizing Permselective Membranes. Trans. Amer. Soc.Artificial Internal Organs 161193-98 (1970) are provided toautomatically regulate the rate of blood ammonia, urea. or other toxicsubstance oxidation of the implanted cell. This hybrid system acts as anartificial metabolic organ to promptly remove the excess ammonia, etc.from a patient without seriously disturbing the body ecology. The samecell may be used in an extracorporeal shunt and. in one embodiment.external DC power is applied for quick removal of excess ammonia. etc.The surgical implantation and shunt providing techniques areconventional and per se do not form a part of this invention.

Two basic types of cells illustrate the invention. and both involve theuse of hydrophobic cathodes. In one alternative. a hydrophilic anodesystem may be used (FIG. I) and in a second alternative a hydrophobicanode may be used (FIG. 2). These electrodes are rendered hydrophobic 0rhydrophilic by controlling the amount of water repellant plastic. e.g.,a polyfluorocarbon such as Teflon." in the electrode structure. Thehydrophobic cathode has a covering membrane of a silicone rubber, apolycarbonate, a polyfluorocarbon or copolymers thereof which permitsdiffusion of the oxygen therethrough as the oxidant. The hydrophilicanode employs a membrane thereover of cellulose or a cation exchangeresin, and is separated from the hydrophobic cathode by an anionexchange membrane or inorganic matrix. In the case of the hydrophobicanode. a membrane of a silicone rubber. a polycarbonate. apolyfluorocarbon or copolymers thereof for diffusion of ammoniatherethrough overlies the hydrophobic anode which is separated from thehydrophobic cathode by an inorganic matrix, the edges of which may becoated with a cation exchange resin to permit diffusion therethrough ofammonium ions.

The entire assembly is adapted for implantation. as by covering thenon-membrane surfaces with a silicone or silastic rubber which hasproven body-compatible properties. Other encapsulating substancesinclude polyfluorocarbons. polycarbonates or copolymers thereof. Theenergy produced by the cell is extremely small since the quantities ofammonia are relatively low. from the power point of view. and the energyis dissipated by standard resistors. These resistors are alsoencapsulated in silicone or silastic. and do not provide sufficient heatthat will cause damage to tissues when implanted.

Another aspect of this invention utilizes an electrochemical cell in anextracorporeal shunt system to rapidly oxidize dialysate-ammoniagenerated by the action of urease on urea in a kidney dialysis unit toharmless, nontoxic nitrogen and water. which are removed by the body byhomeostatic processes.

As indicated previously. there have been recent developments in urearemoval in hemodialysis that involve the action of urease on urea withthe release of large quantities of ammonia as a product. The presenceofa high ammonia concentration in the dialysate would rapidly lead toreverse dialysis of ammonia and marked increases in the patients bloodammonia level. The ammonia can be removed by an electrochemical cell aspreviously described, while maintaining the advantage that a smallvolume of water. which is recycled. can replace very large volumes ofexpensive dialysis fluid. The bulk of equipment is thus also markedlyreduced. The ammonia removal system of this invention overcomes themajor difficulty of the proposed adsorption or ion exchange systems inthat their sorbent-loaded cartridges are eliminated and replaced by theelectrochemical cell.

In another embodiment of this invention, an extracorporeal shunt systemcontaining an electrochemical cell with urea selective anodes rapidlyand directly oxidizes. electrochemically, the dialysate-urea inhemodialysis to harmless nontoxic products such as carbon dioxide.nitrogen and water which may be reabsorbed by the patient and removed byhomeostatic processes. This electrochemical cell is preferably on aclosed dialysis loop.

DETAILED DESCRIPTION FIG. 1 shows schematically. partly in section andpartly in plan view. an implantable cell in accordance with thisinvention having a hydrophobic cathode and hydrophilic anode. Thedetoxification unit I comprises the oxidizing cell portion 2. and theenergy dissipating section 3. The hydrophobic oxygen cathode 4 employshydrophobic catalysts such as hydrophobic silver. silver oxide, gold orother catalysts inert to ammonia. The outer surface of the cathode iscoated with a layer of silicone rubber. for example, Medical TypeAdhesive silastic by Dow-Corning Company. coating 5 shown in FIG. 1.

The hydrophilic anode 6 is relatively ammonia selective. and typicallymay be hydrophilic platinum. The anode is coated with a layer ormembrane of cationic exchange resin 7. At pH of 7.4. virtually all theammonia present in body fluids is the form of ammonium ions. NH Thecation exchange layer 7 on the hydrophilic anode 6 allows positivelycharged ions such as H and NHI to pass through. while at the same timenot permitting passage or transport of organic substances such asglucose in the body fluids to the anode. With the coatings of siliconeand cation exchange membranes over the anodes and cathodes. the cellportion 2 is adapted for implantation in the body.

The cell sandwich 2 also includes an anion exchange membrane 8 as aninternal electrolyte in intimate contact with, and sandwiched between.the anode and cathode. Note that the silicone or silastic coating 5 onthe cathode 4 covers the edges of the anion exchange membrane 8, as at5A and 58. Although the schematic FIG. 1 appears relatively bulky. inactual practice. as seen better from FIGS. 3 and 4, the actual cellportion is wafer-thin. A typical cell has an exposed anode or cathodearea on the order of 1 inch in diameter. and may be 3 millimeters thick.An alternative silicone material which may be used is Dow-Corning3144RTV adhesive/sealant. which is a translucent. room temperaturevulcanizing (curing) silicone rubber adhesive. which is noncorrosive tocopper.

The operation of a detoxification cell. e.g.. a deammonation cell.implanted in the body. is as follows: Oxygen molecules and water vaporfrom the body fluids as shown to the left of the cell in FIG. I diffuseacross the silicone rubber membrane 5 to the hydrophobic cathode 4 wherethey are reduced to form OH ions. The OH ions naturally migrate acrossthe anion exchange membrane 8 as shown in this figure to the hydrophilicanode 6. At the same time. ammonium ions from the body fluids diffusethrough the cation exchange layer 7 on the anode 6. These NH. ions thenare electrochemically oxidized at the interface between the anode andthe anion exchange membrane. In the process. electrons are given up tothe current collector of the anode and are transported in the externalcircuit portion 3 of the cell. The reaction products N and H 0 diffuseout back through the cation exchange membrane and are removed by thehomeostatic processes of the body. It will be noted that this cellsimultaneously functions as a water pumping device to keep the cathodedry as well as oxidize the ammonia to nitrogen. This dry cathode systemallows the electrochemical cell to operate with effective oxygen masstransfer thereacross.

The electrons released at the anode 6 are transported by a currentcollector (E.G. gold x-met) internal to the cell 2 and part of the anodeassembly 6 to external wire 9. These electrons are transported by thewire 9 to a current consuming device 10., for example. a resistor. Theresistor dissipates the energy released from the oxidation of theammonia at rates and temperatures which do not cause physiological harmto the body. The external circuit is completed by wire 11 passing to thecurrent collector portion of the cathode 4. In an alternative. thisexternal energy dissipating section 3 may also contain. as part of ahybrid unit. a rechargeable storage battery and resistor systemconnected parallel with the resistor 10. This system permits energy tobe stored for monitoring the blood and tissue ammonia level. and tofreshen the catalysts of the electrodes and is illustrated in detail inFIGS. 9A and 98. While the term external has been used, it should beunderstood to be used in context in connection with the cell. and thatthe entire deammonation unit I is not, in this example. external to thebody. Thus. the entire energy dissipating section 3 is convenientlyencapsulated with physiologically acceptable materials such as the abovementioned silicones. The anodic, cathodic and overall reactions forammonia detoxification are illustrated by the equations 1 3 below:

E 1.17 (Overall Reaction) FIG. 2 is a diagram, in part in schematic. fora second embodiment of the invention which employs a hydrophobic anode.The cathode of the invention is as above described. However, the anodeI5 is a hydrophobic catalyst-containing anode which is covered with agas permeable membrane or layer 16 (e.g. silicone rubher), which ispermeable to gaseous ammonia dissolved in the body fluids. The oxygen isalso dissolved in the body fluids and both are supplied to the cathodeand anode respectively. in the gaseous" state. The cell sandwich alsocontains an inorganic matrix solid electrolyte separator 17 between thehydrophobic cathodes and anodes. The outer surface of both the anodesand cathodes are coated with a thin layer of silicone rubber, 5 and 16,respectively. The edges of the inorganic matrix separator I7 are coatedwith cation exchange resin I8, 18. The NHK ions from the body fluids aretransported across the cation exchange resin 18, 18. at the edge of thecentral inorganic matrix separator which acts as a solid. yet permeableelectrolyte. Within the separator 17, the equilibrium NH, NH, H favorsthe formation of NH since H combines with OH ions produced at thecathode to form water molecules. The separator 17 thus also serves as anNH gas generator. Accumulated water molecules diffuse across the cationexchange resin 18, 18' to the exterior of the unit. This outward flow ofwater from the separator to the body fluids provides a low viscosityenvironment around the entire unit which enhances the mass transfer ofNH, ions, 0 and N molecules.

The OH ions which are needed for the anodic oxidation of NH;, and formaintaining a high pH in the separator are produced from the cathodicreduction of 0. The anodic, cathodic and overall reactions are as aboveshown in equations 1 3. The electrons produced by the anodic reactionare passed as before to the external" energy dissipating portion of thecell 3 via wire 9 and resistor 10. The external circuit is completed andprovides electrons for the cathodic reaction, Equation 2 above, via wire11. As described above, a silicone coating 19 may be used to encapsulatethe wires and resistor external to the oxidizing cell portion of thedeammonation unit 1.

The electrochemical cell portions 2 of the entire deammonation unit 1 asabove described in connection with FIGS. 1 and 2 may be arranged inparallel into a multicell assembly which is then hybridized byconnection to a rechargeable storage battery and a potentiostat. See forexample, FIGS. 9A and 9B. The storage battery per se is relativelyconventional, and per se does not form part of this invention.Typically, it may be nickel cadmium cells of appropriate capacity, suchas in a battery which will store a high percentage of its full charge ata potential of approximately 0.4 volts. When the deammonation unit isoperating at a peak rate of ammonia removal, the electricity generatedby the oxidation of the ammonia is stored in the battery. When there isa low ammonia concentration, electricity from the storage battery is fedback to the cell assembly by virtue of reversing polarity of the batteryconnection to maintain a constant potential and constant rate of ammoniaremoval. Provision for measurement, and/or recording the magnitude anddirection of the current in the feed-back system provides a monitor ofblood or tissue ammonia level. An alternative to the Ni-Cd or otherstorage battery is the case where a (glucose) bioautofuel cell isimplanted as part of the system to produce a driving current source byoxidation of glucose in body fluid. This bioautofuel cell per se is notpart of this invention and is described above in the Wolfson et alarticle 16 TASAIO 193-198.

As noted above, this cell is particularly adaptable for implantationwithin the body. However, the units may be employed as a device for fastblood-ammonia removal in conjunction with a hemodialyzer of conventionalconstruction, which, per se, does not form a part of this invention. Theammonia selective anodes as above described may be connected to varioustypes of cathodes which may utilize the oxygen from the blood directly,or may be provided with an external air or oxygen supply. An externaldirect current is applied to the cell to speed up the electrochemicaloxidation of the blood ammonia to nitrogen and water at the anode. Theuse of such DC power supply provides a means of fast ammonia removal forcases of severe hepatic failure.

ADDITIONAL EMBODIMENTS FIG. 4 illustrates in section view a cell of thisinvention in a folded configuration to increase the surface area of thecell. Anion exchange membrane 8 is sandwiched between a pair ofcatalyst-filled X-Met or screen current collectors with the catalystside facing the membrane 8. The current collector with catalyst formsthe anode and cathode assemblies 6 and 4 respectively. The cathodeassembly 4 is overcoated or covered with a silicone rubber membrane andthe anode assembly 6 with a cellulose membrane 22. This cell may be usedimplanted or extracorporeal. For example, the cell may be connected toan arteriovenous shunt in the radial artery such as is used inhemodialysis. In the alternative, the cell may be implanted in theperitoneal cavity and connected to the internal iliac artery and vein.

FIGS. 5 and 6 illustrate typical implantation sites, with FIG. 5 showingthoracic cavity or subcutaneous sites. and FIG. 6 showing typicalabdominal cavity sites. A unit 1 may be placed in the subcutaneous fatpad 23 in a manner similar to a cardiac pacemaker implant. Otherlocations involve placement (by suturing a flap of silicone rubbermolded on the unit 1) intrapleurally, e.g., in the apex of the pleuralcavity 24 or in the costophrenic angle 25, intrapericardially, e.g., inthe pleural pericardium 26 or the diaphragmatic pericardium 27. Thecells may be preshaped to conform to the receiving cavity or site, asabove noted in FIG. 4.

FIG. 6 illustrates typical locations for the units within the abdominalcavity, for example, subdiaphragmatic attachment to the diaphragm nearthe coronary ligament 28. In the lesser sac. the units may be suturedinto place on the lesser omentum 29, or theposterior abdominal wall 30.In the greater sac, the unit may be placed on the lesser omentum at 31,on the anterior abdominal wall at 32 or the posterior wall at 33.

FIG. 7 illustrates units assembled in an extracorporeal shunt unit 34.Housing 35 has provision for blood inlet 36 and blood outlet 37, air or0 inlet 38 and exhaust air or 0; outlet 39. Manifolds 40 and 41 serve todistribute and collect, respectively, the blood to the anode side 22 ofthe cell portions 2. Baffles 42 close off the edges of the blood andoxygen spaces on alternate sides. The cells are oriented with like facesfacing each other and thus alternate with respect to top and bottom ofunit. Manifolds 43 and 44 likewise distribute and collect, respectively,air or 0 to the cathode side 5 of the cell portions 2. Bus bars 45 and46 are connected respectively to the current collectors of the anode andcathode current collectors. respectively (not shown) and wires 9 and IIare connected across a DC power source, such as a battery, to provideenergy for rapid oxidation of the toxic substance such as ammonia. Thiselectrical schematic is illustrated in FIG. 8 in which cell 2 isconnected in parallel across resistor 47 and variable external powersource 48.

FIGS. 9A and 9B show two modes of a hybrid system embodiment of thisinvention for completely implanted units. Cell 2 is connected inparallel with resistor 10, and to batteries 49 and 50 as abovedescribed. Switch units A and B are pottable solid state switchingcircuits. here represented for simplicity as ganged switches.

Switch A reverses polarity and switch B changes the connections fromseries to parallel and vice versa. The change of state of these switchunits from the mode shown in FIG. 9A to that in FIG. 9B is dependent onthe potential difference across the cell 2 and resistor 10 as shown bythe reference V. The mode of FIG. 9A illustrates the circuitry settingfor a condition of high ammonia concentration with the secondary cells49 and 50 being charged by the cell 2 in a parallel configuration due tothe high rate of ammonia oxidation. As the voltage V, across the cell 2drops, the state of the switches is triggered to that of themode shownin FIG. 9B. In this mode the secondary cells 49 and 50 discharge inseries through the cell 2 to increase the current, driving the cell 2 toincrease ammonia oxidation. By the addition of two more switches inswitch circuit B for each additional secondary battery cell, the numberof secondary cells can be increased to achieve the desired drivevoltage.

In FIGS. 10, I1 and I2, the above-described electrochemical cells may beemployed in any conventional extra-corporeal shunt system as a devicefor fast dialysate-ammonia removal. The ammonia selective anodes in thecell are as described previously and may be connected to various typesof cathodes which utilize oxygen directly from the dialysate, or thecells may be provided with an external air or oxygen supply 56 asillustrated in FIG. 10. The cell units may also be filled withurease-loaded microcapsules as illustrated in FIG. 11 instead of beingconnected to a separate upstream urease-loaded cartridge as shown inFIG. l0. After flowing through either system illustrated in FIGS. 10 andII, the deammonated dialysate 531 will be recirculated for repeatedremoval of uremia waste metabolites. An external direct current may beapplied to the cell units to accelerate the electrochemical oxidation ofthe dialysate ammonia to nitrogen and water at the anode.

More particularly, referring to FIG. 10, blood from a patient is passedinto a conventional hemodialyzer 51 by conventional conduits 50 and 52wherein blood waste products are removed by a constantly circulatingdialysate flowing in closed loop 53 through the pumping action of pump54. The dialysate, as it leaves the hemodialyzer 51, is first contactedwith urease capsules contained in urease reactor 55 to convert urea toammonia. The dialysate containing ammonia is then passed to ammonia cell58, similar in construction to the cell illustrated in FIG. 7 andconnected to a suitable DC power source wherein the ammonia is oxidizedby gaseous 0 (i.e., air) entering inlet 56. Unused oxidant and inertsare continuously expelled through exhaust conduit 57. The ammonia isoxidized in cell 58 to nontoxic nitrogen and water which are ultimatelyexpelled by the body by normal homeostatic processes.

In a preferred embodiment illustrated in FIGS. 11 and 12, the functionof urease reactor 55 is incorporated directly into cell 58. Cell 58 issimilar in construction to the cell illustrated in FIG. 4 except thaturease capsules 61 are packed between convoluted individual alternatingcells defined by anode 59 and cathode 60. In each individual cell, thecathode 60 and anode 59 are separated by a suitable anion exchangemembrane 62.

As mentioned previously, the electrochemical cells may be employed in anextracorporeal shunt system as a device for fast dialysate-urea removal.The ureaselective anodes may be connected to various types of cathodeswhich utilize oxygen from the dialysate directly, or from an externalair or oxygen supply. After passing through a hemodialyzer and theelectrochemical deureator, the deureated dialysate is then recirculatedto the hemodialyzer for repeated removal of uremia waste metabolites. Anexternal DC current may be applied to the cell units to speed up theelectrochemical oxidation of the dialysate-urea to nontoxic productssuch as carbon dioxide, nitrogen and water at the anode. As a result,the whole dialysis system is made portable.

In more detail. the direct removal of urea from dialysate isschematically illustrated in FIG. 13 where blood flows throughhemodialyzer 51 through conduits 50 and 52 to selectively transfer ureaand other impurities to the dialysate flowing in closed dialysate loop53.

In the cell in this loop. the dialysate contacts an anode 73 (which, forexample, may be of similar construction to that structure illustrated inFIG. 7). Cathode 74 is contacted with air flowing into cell 70 throughconduit 71 and exiting through conduit 72. As a result, the urea isconverted to harmless CO N and water. The conversion rate of urea byanode 73 can be increased by driving the cell through DC power supply 76which is connected to cell 70 by leads 75, 75'.

EXAMPLE I The following example has reference to FIG. 3 which shows inexploded perspective an electrochemical cell in accordance with thisinvention having an anode and cathode of 1 square centimeter area. Theunit as shown is of the type illustrated specifically in FIG. 1. Clampedbetween rings 20 and 21 by means of screws 13 are the following partsreading from left to right: The cellulose membrane 22 lies over theanode assembly 6 which comprises a gold X-Met current collector 6A intowhich is impregnated platinum and Teflon powder 68 as the anode catalystmaterial. The external wire circuit 9 is connected to the gold currentcollector 6A. The anode assembly is in contact with a quaternaryammonium anion exchange membrane 8 which is contained within a siliconegasket rim A. This in turn lies against the cathode assembly 4 whichcomprises a silver X-Met screen current collector 4A into which isimpregnated a silver and Teflon powder 4B. The external circuit wire 11is attached to the silver screen. A silicone rubber membrane 5 is placedover the exterior surface of the cathode assembly 4. The righthand ring21 completes the assembly which is screwed together to insure goodcontact of the parts. The edges of the assembly and the external wiresmay be then painted with a silicone (medical type A) adhesive or theDow-Corning 3144RTV adhesive/sealant.

The cell was immersed in a Krebs-Ringer bicarbonate buffer solution ofpH 7.4. The oxygen concentration in the buffer was the same asphysiological. that is. 85 Torr. Ammonium chloride at a concentration of60p.M provides an NH, concentration of about lug/ml. Under theseconditions, the cell exhibited an open circuit potential of 0.40 voltsat room temperature. In operation. the cell exhibited a potential of0.22 volts at a constant current density of 22;.LA/cm With theseoperating properties. a deammonation unit having an electrode surfacearea of cm operating at l mA/cm'- would clear up a total of 20 mg.ammonia in about 4 hours. The arterial ammonia level of a patient wouldfall from 4;.Lg/ml in such a 4 hour run to about 2;.Lg/ml. In anapproximate run of another I 2 hours. the normal blood level of about[p.g/ml would be achieved.

EXAMPLE II The following example has reference to FIG. 13 wherein ureais directly oxidized electrochemically without prior enzymatichydrolysis with the end products being N CO and H 0. The experiementsperformed involved: linear potential scans of ammonium chloride, urea,and glucose plus urea. in phosphate buffer solutions. and anodicoxidation of glucose-urea in bicarbonate buffer in extracorporealelectrochemical cells.

An Electrochemistry System Model I70 scanner (Princeton Applied ResearchCorp.) was used for the linear potential scanning studies. The system issimilar to the one employed in previous studies on anomeric effects inthe electrodic oxidation of carbohydrates. (Yao. S. J., Appleby. A. J.and Wolfson. S. K., Jr., Zeitschrift fur Physikalische Chemie. (NeueFolge) 82; 225-235, 1972) The working electrode (i.e.. electrode beingevaluated) was a disc of 1 cm smooth platinum. Ag/AgCl was used as thereference electrode of known potential. The counter-electrode was a 4 cmplatinum black (40 mg Pt/cm The electrolyte was Krebs- Ringer phosphatebuffer at pH 7.4. Triangular potential sweeps were conducted over arange of -l.00 v to +1.00 v vs. Ag/AgCl. i.e., 0.32 v to +1.68 v vs. RHE(Reversible Hydrogen Electrode potential at the pH of the solution at ascan rate of0.20 v/sec. Potential/current curves were recorded on eitheran oscilloscope or an recorder. The potential sequence used to achieve awell-defined Pt surface followed from that of Giner and Malachesky.(Giner, .l. and Malachesky. R., Proc. Artif. Heart Program Conf., US.Dept. Health, Education and Welfare. 1969, pp. 839-848) The generalcharacter of the scan also closely resembles similar plots obtained inphosphate buffer by Giner and Malachesky. FIG. 14 shows the cyclic scanrecorded for 2.0 M urea in a phosphate buffer. A time-invariantoxidation peak appears at around 0.12 v vs. Ag/AgCl (i.e., around 0.80 vvs. RHE) in the anodic scans of the urea solution. The same peak appearsin the glucose plus urea solution (0.80 M glucose and 2.0 M urea) but isnot seen in the scans of both solutions of buffer alone and of NH,Cl.The chemisorbed species at 0.80 v vs. RHE is believed to be reduced COas produced by the urea adsorption. As a result, the urea is directlyoxidized at a Pt anode with the products of the oxidation being CO N andH 0. NHf, N0 and N0 were not found to be products of the anodicreaction.

EXAMPLE III Experiments on deureation by anodic oxidation were carriedout in extracorporeal electrochemical cells. This cell was made of asandwich of electrodes and permselective membranes and assembled in aflow-thru system similar to FIG. 7. The sandwich consisted of ahydrophilic Pt -black anode, an anion exchange membrane and ahydrophobic Pt -black cathode.

The anion exchange member was an AMFion A-l00 membrane manufactured byAmerican Machine and Foundry Co., Stamford, Connecticut. This membranehas a polyethylene backbone containing polyelectrolytes of quaternizedammonium thereby rendering the membrane permeable to negative (anion)groups.

The Pt-black anode was manufactured from a paste of porous platinumblack having a surface area of 25 M /g in 25 percentpolytetrafluoroethylene (Teflon) by pressing the paste, withoutsintering. to 200 psig over a gold X-Met current collector. Theresultant anode had a thickness of 25 mils and contained 15 g/ft of Ptblack.

The cathode was manufactured from a paste of porous platinum black (25M' /g) and 25 percent Teflon by pressing the paste, with sintering tocure the Teflon, at 2,000 psig over a gold X-Met. The resultant cathodecontained 15 g/ft of Pt black and was painted with silicone so that itwould be porous to gas only.

The anode was covered with a cellulose membrane and was exposed to aflowing glucose-urea solution or plasma-dialysate (P0 of mm Hg, Pco of36 mm Hg and at pH 7.4). The cathode was in direct contact with flowingair. Current flow was produced either by shunting the cell with aresistor or by the application of an external power source (D.C. FIG. 15shows the effect of added urea (5 mM) on an electrochemical celloperating with 5 mM glucose in bicarbonate buffer at the Pt anode.flowing air at the Pt cathode and under 5 K ohm passive load. The cellvoltage went up from 0.41 v to a maximum at 0.57 v within I2 hoursfollowing addition of the urea to the glucose solution. Similar voltageenhancement by the effect of addition of plasma or its dialysate. bothcontaining urea, to an operating implantable glucose fuel cellconsisting of a Pt anode and an 'Ag cathode was also observed.

The above example shows that urea can be anodically oxidized to endproducts such as CO N and H 0 by an extracorporeal electrochemicaldeureator which utilizes Pt-black or other catalysts, electricity andair. This approach eliminates the step of action of urease on urea andthe need for an expensive adsorbent such as zirconium phosphate toremove the NH, thus formed. As a result, the entire renal dialysissystem may be made portable.

EXAMPLE IV The role of elevated levels of normal blood and tissuecomponents upon the function of an implantable glucose fuel cell(bioautofuel cell) is demonstrated in this example. Components studiedincluded urea, creatinine, alanine, ammonia and a frequently ingestedabnormal substance, ethanol. The effect of these specific substancesand/or plasma, plasma dialysate and plasma residual after dialysis on anoperating glucose fuel cell was determined.

Briefly, most of these substances inhibited the performance of fuelcells containing platinum catalysts exclusively. However, the use of anO -specific cathode (Ag) prevents such inhibition.

lnitially, plasma, plasma dialysate and the plasma macromoleculeresidual after dialysis (mostly proteins and glycoproteins) areseparately added to an in vitro glucose fuel cell operating undercontrolled conditions and having the anode covered with a membrane,i.e., cellulose film similar to a dialysis membrane. Thereafter, theeffects of several specific normal constituents of plasma ultrafiltrateon the cell were determined when added individually to the glucose fuelcell. Also, several abnormal" substances were similarly studied. Thesesubstances were ones (such as ethanol and ammonia) which can be presentin body fluids under certain circumstances such as after imbibingalcoholic beverages and in disease states such as acute or chronichepatic failure (hepatitis or cirrhosis).

Two types of in vitro fuel cell systems were employed. The first type ofcell was composed of separate half-cells where electrodes consisting ofsuitable catalysts were immersed in beakers containing a simulated bodyelectrolyte (Krebs-Ringer-bicarbonate). [n this half-cell system, thehalf-cells were connected by agaragar saturated UCl bridges. The anodewas provided with glucose in a physiological concentration (5 mM) andequilibrated with a mixture of 5 percent CO and balance N (pH 7.4.PC();; 35-40 torr, P 5 torr). The cathode was immersed in a similarfluid equilibrated with a mixture of 5 percent CO 12 percent 0 andbalance N (pH 7.4, Pco 35-40 torr, P0 torr). When the cell charged to astandard operating level of about 50 microamps/cm through a 540 K ohmload, the test substance was added to the anode or cathode half-cell.

The second system employed an implantable sandwich cell with anode andcathode compressed in a wafer configuration with an anion exchangemembrane between as illustrated in FIG. 3. The cell wasimmersed in asingle beaker containing Krebs-Ringer-bicarbonate electrolyte andequilibrated with gas as above (pH 7.4, Pco- 35-40 torr, P0 85 torr). Inthis cell the anode was covered by a cellulose film (Nephrophane, asodium-cellulose-xanthogenate membrane manufactured by FilmfabrikWolfen, East Germany) and the cathode by l0 mil silicone rubber, medicalgrade, adhesive film (Silastic, Cat. No. 500-36 HH 0806 as manufacturedby Dow-Corning). The cathode operates dry by virtue of the fact that thecovering membrane admits only gas vapors. and the anion exchangemembrane electrolyte conducts OH (produced by reduction of 0 away fromthe cathode to the anode where product water is formed by combinationwith protons liberated by oxidation of fuel (glucose). In this case,test substances were added to the electrolyte and had simultaneousaccess to both anode and cathode covering membranes.

The test substances were of two kinds. The first is a number ofindividual specific compounds as described in detail below. The secondis whole plasma, and plasma products obtained by dialysis. For thispurpose, whole human plasma was obtained from a blood center. The bloodhad been collected in a bag containing 67.5 ml ACD anticoagulantsolution (0.8 percent citric acid, 2.2 percent sodium citrate and 2.45percent glucose). This resulted in a glucose concentration of 455 mgpercent in the plasma after separation. A portion of the plasma wasdialyzed overnight at 4C vs the same buffer used in the tests withindividual substances. The dialysis was carried out by placing ml plasmain a cellulose dialysis sac (AHT Co., 1 inch dialysis tubing 0.0008 inchthick) which should retain substances of MW 12,000. This tubing wasthoroughly washed with water to remove all traces of glycerol beforeuse. The dialysate was then further diluted with an equal volume ofbuffer before being placed in the test cell. Concentrations of itsvarious components are listed in Table 1.

TABLE 1 Composition of Fluids Used for Plasma Studies of Example 4Starting Material Final Concentration in Cell Macro- Whole Plasmamolecular Plasma Dialysate Residual Exp. l Exp. ll Exp. lll

Protein (gm 6.4 0* 5.6 1.2 0 1.2 Glucose (mg 455 157 0* I53 154 153 Urea(mg 22 8 0 4 4 0 Creatinine (mg 1.0 0.3 0* 0.2 0.2 0 Uric Acid (mg 3.7l.l 0* 0.7 0.6 0 Chloride (mEq/l) 73 I09 H7 H8 119 I26 Sodium (mEq/l)160 152 149 149 M7 Potassium (mEq/l) 3.9 5.0 6.6 8.3 6.7 7.7 Phosphate(mEq/l) 3.2 3.7 3.6 3.5 3.7 3.6 Calcium (mg 9.2 2.9 0* 1.7 1.5 0 Alk.P'ase. (Units) 100 0* 94 19 0 20 Cholesterol (mg I45 0* I30 27 0 27These values were less than the lower limit of detection on theauto-analyzer and are presumed to bc essentially zero.

We then tested whole plasma diluted in a manner so that the dialyzablecomponents of the plasma were present in the same concentration as theywere in the dialysate-only test. This renders differences in the re- Itwas shown that within the first six hours. there was no appreciablebacterial growth or diffusion of added substances across the saltbridge; therefore, the 6-hour time interval was chosen as a standardtesting period.

sults dependent only upon the presence or absence of At the normal levelof concentration, none of the subplasma macromolecules. This wasaccomplished by stances tested exhibited a poisoning effect on thecells. using a final dilution of plasma which provided the Creatininepoisoned the anode at the abnormal consame concentration of glucose.urea. etc.. as in the dialcentration. it was observed that all Pt/Pt(anode/cathysate test. The third experiment in this series involved ode)cells experienced poisoning when abnormal conthe addition of only theplasma protein. To this end the it) centrations of the above substanceswere present at dialysis of the plasma was continued after removal ofboth anode and cathode. In general. no poisoning was the originaldialysate. The buffer was changed 5 times observed when the cells weremade of Pt anode and Ag over a period of 72 hours to remove remainingamounts cathode. of dialyzable substances. We adjusted the plasma pro-Effects of added endogenous substances on Pt/Pt and tein concentrationto that of the whole plasma experi- Pt/Ag sandwich cells at roomtemperature and at 37 C ment to render all the tests comparable. Thus.the conare illustrated in FIG. 16. None of the substances centration ofsubstances common tomore than one of caused appreciable poisoning of thePt/Ag sandwich the experiments was always approximately equal. Glucells.Urea and ethanol seemed to enhance the percose was added. as needed. tokeep its concentration at formance of these operating cells at higherconcentra- 8.5 mM 154 mg percent) in all 6 cells. 20 tions. The voltagevalues demonstrate that ethanol. The substances investigated in the 5 mMglucose cell ai l l g g 3 f were creatinine. alanine. ethanol. ammoniumchloride. 5: g Sue 8 a i urea. diluted whole plasma. plasma dialysateand mac- MC Ce 5 were polsone 0 l egress I by these added substances andshow specificity of the romolecule residual.

Pt/Ag cells of this invention. These results are consis- The agaHtgarKCl ridg type C s r uscd to tent with those of the salt-bridge type fuelcells and termine the individual effects on either the anode or l ly idi ate that poisoning i occurring at the Ptthe cathode of an operatingglucose fuel cell 10 K ohm athode where adsorption and oxidation of theadded load). Either hydrophobic silver (Ag) or hydrophobic s btance'take place. platinum (Pt) was used as the cathode while hydro- Webelieve that the presence of these substances at philic platinum wasused as the anode in all cases. North Pp th d lt i od t tion thu mal andabnormal amounts of various test substances a i a d tion f lt der l dingondiwere separately added to either the anode. the cathode {ions Th dd dsubstances did not ff t th ltor both half-cells at room temperature. Theresults of bridge itself or the anion exchange membrane since voltagechange during a 6-hour run under l0 K ohm both salt-bridge and sandwichtypes of Pt/Ag cells were load following this addition are compiled inTable 2. not poisoned.

Table 2 Separate Additions of Substances to Salt-Bridge Type Anodeand/or Cathode Half-Cells (Room Temperataure)* Pt/Pt Pt/Ag Anode CathodeVoltage Anode Cathode Voltage mg7l mg72 (v) mg% mg% (v) Creatinine 0 O0.60 0 O 0.33 l 0 0.60 l O 0.33 2 0 0.50 2 0 0.33 2 l 0.33 2 2 0.43 2 20.30 Alanine 0 0 0.54 0 0 0.40 3 0 0.54 3 O 0.40 4 0 0.52 4 0 0.31 4 30.38 4 4 0.50 4 4 0.36 Ethanol 0 0 0.66

100 0 0.67 1000 0 0.43 1000 0 0.68 1000 [00 0.39 1000 100 0 I000 10000.42 Urea 0 0 0.60 0 0 0.42 20 O 0.60 20 0 0.42 0 0.58 40 O 0.42 40 200.42 40 40 0.54 40 40 0.41 Ammonium Chloride 0 0 0.58 0 0 0.40 0.5 00.58 0.5 O 0.40 2.5 0 0.56 2.5 O 0.40 2.5 0.5 0.40 2.5 2.5 0.53 2.5 2.50.38

Low values were chosen to be in the normal rangc of human blood. Highvalues were those which might be present in abnormal states. (Ethanolvalues imply social and excessive drinking.) Logistics were such thatthe data for empty spaces were not obtainable in the same electrolyteand fuel mixture. Since the substitution of Ag for Pt in the cathodeimplies no change in anode performance, it is possible to evaluatc theeffect of substances added to the cathode alone without repeating thezero and low concentration of the substance in the anode.

Further. our experimental results show no appreciable Cl poisoning assuggested by other researchers. The prevention of such poisoning at theAg cathode is attributed to the drycathode design of the fuel cell ofthis invention. The rationale of this particular design is that theanion exchange membrane (AlEM) does not just serve as an internalelectrolyte or separator. it is also a component of a pumping mechanismto drive the OH ions (produced from the cathodic reduction of or.indirectly. drive the H 0 from the cathode to the anode. Thus. with theexception of the immediate cathode/AIEM interface, the cathode can bemaintained dry. Furthermore, at the interface. the high concentration ofOH ions present there could prevent the formation of AgCl. Therefore. itis believed that the Cl ions do not actually reach the Ag catalyst andthus no Cl" poisoning can occur.

A study of the effect of substances in human plasma was carried out withboth Pt/Pt and Pt/Ag sandwich type cells at 37 C. Table l is a partiallist of the substances present. The plasma and plasma dialysatecontained many other usual substances which were not analyzed. and arenot listed since conventionally present in plasma or dialysate.Experiments were performed on solutions of the whole plasma. plasmadialysate and the macromolecule residual from the dialysis of theplasma. Results of the three experiments are illustrated in FIGS. l7, l8and 19 respectively. It was observed that during the 10 hours afteraddition of the whole plasma or the dialysate to the glucose fuel cellsoperating under l0 K ohm load. the voltage of the Pt/Ag cells rosesteadily and that of the Pt/Pt cells was swaybacked. dipping initially.and then rising above initial voltage values. The voltage of the Pt/Ptcells soon reached a maximum and then relatively quickly (in a fewhours) fell to zero. On the other hand, the perfoi'mance of the Pt/Agcells shows no such adverse effect. In the Pt/Ag cells. the voltage alsofell somewhat after the maximum was reached. but at a lower rate. andthe cells also attained a relatively constant level of voltage (or poweroutput). In contrast, the Pt/Pt cells declined to substantially zero.

We discovered that urea was causing the enhancement of operatingvoltage. Thus, in the third experiment of this series (macromoleculeresidual). the Pt/Pt and Pt/Ag cells were operated for 17 hours in abuffer solution containing 1.2 g percent residual protein and 154 mgpercent glucose but no urea (See FIG. 19). By this time a relativelyconstant voltage had been reached. 4.0 mg percent urea (sameconcentration as that of the dialysate experiment) was then added toeach cell. The Pt/Pt cell voltage fell rapidly to zero while the Pt/Agcell voltage rose steadily from 0.46 v to a maximum of 0.64 v within 12hours. The operating voltage of this cell stayed constant at 0.64 v witha power output of 4lpwatts for at least 30 hours before the cell wasterminated. This shows the ability of the cells of this invention -toutilize, the thereby detoxify. urea. as is expected from the discussionabove on deammonation. The urea-poisoned Pt/Pt cells were taken out andsoaked in water overnight before they were reimmersed in fresh glucosebuffer. These cells were found to be regenerable.

In its broadest aspect. the invention thus involves the use ofelectrochemical cells in the manner of artificial organs to detoxifytoxic substances the body is unable to metabolize. In addition toammonia and urea. uric acid. creatinine. alanine. drugs such asdigitalis glycosides or barbiturates. and toxic agents such as methanoland ethanol may be oxidized to nontoxic products such as N H O, acetateand CO Diabetic acidosis could be improved by oxidizing ketone bodiesand aceto acetate to CO and water. This method will detoxify oreliminate any substance which is oxidizable to harmless or less harmfulproducts and which can be selectively or non-selectively admitted to theanode by means of specific or non-specific covering membranes. The anodeitself may also be selective with respect to the toxic substance to beeliminated.

in should be understood that various modifications can be made withoutdeparting from the spirit of the invention. and the scope thereofdetermined by the appended claims which should be interpreted as broadlyas the prior art will permit. and in the light of the specification ifneed be.

We claim:

1. A method of treating patients having metabolic imbalances comprisingthe steps of:

a. selecting a patient having relatively high concentrations ofoxidizable toxic substances which their bodies are unable to metabolizeor remove to substantially non-toxic levels.

b. said toxic substances being present in extracellular fluid in atleast one natural bodily fluid zone selected from the circulatorysystem. the pericardial sac. the abdominal peritoneum. the pleuralcavity. and intratissue regions.

0. surgically preparing said patient to provide said extracellular fluidfrom at least one of said natural bodily fluid zones,

d. contacting said extracellular fluid with an electrochemical cellsystem adapted to oxidize said toxic substances to non-toxic ormetabolizable substances.

e. maintaining said contact for a time sufficient to reduce the amountof said substances to relatively non-toxic substances in said patient.and

f. permitting said detoxified extracellular fluid to return to aphysiologic environment in said patient.

2. A method as in claim 1 wherein said toxic substances are selectedfrom NH, Nl-lf'. urea. uric acid, digitalis glycosides. carbon monoxide.barbiturates. ketone bodies. aceto acetate. methanol. creatinine.alanine. ethanol. and mixtures thereof.

3. A method of treating patients as in claim 2 wherein said toxicsubstances are selected from urea. uric acid. NH NH. and mixturesthereof and said electrochemical cell system is adapted to oxidize saidNH or NH. to nontoxic N and H 0 for a time sufficient to reduce said NHor NH,* to relatively safe levels.

4. A method as in claim 1 wherein said step of contacting includespassing some of the blood of said patient through an extracorporealshunt in which said electrochemical cell is disposed.

5. A method as in claim 3 which includes the added step of supplying DCcurrent to said cell to increase the rate of oxidation of said toxicsubstances in said elec- -trochemical cell.

6. A method as in claim 3 wherein said electrochemical cell systemincludes a cathode assembly. and which method includes the added step ofsupplying air or oxygen to the cathode assembly of said cell.

7. A method as in claim 3 wherein said cell is adapted for implantationand includes an oxygen permeable membrane in association with a cathodeassembly. a membrane permeable to said toxic substances disposed inassociation with an anode assembly, and an ion transfer membrane betweensaid assemblies, and said cell is disposed in said body so that saidmembranes'are in contact with said extracellular fluid.

8. A method as in claim 7 wherein said cell is implanted in a manner sothat said anode membrane is exposed to blood of said patient.

9. A method as in claim 3 which includes the steps of:

a. Monitoring the output of said cell system as a measure of thepatient's toxic substance concentration. and

b. Selectively supplying current to said cell when said monitoredconcentration reaches a predetermined level to promote oxidation of saidsubstance.

10. A method as in claim 1 wherein said cell system includes ahydrophobic cathode assembly containing a high surface area metalconsisting essentially of silver and an anode assembly containing a highsurface area metal comprising platinum.

11. A method as in claim 2 wherein said toxic substances are NH;, and NHgenerated by the action of urease on dialized urea in a hemodialysisfluid.

12. A method as in claim 11 wherein said step of contacting includespassing the dialysate of said patient through urease in a closed loopcircuit in which said electrochemical cell is disposed downstream ofsaid urease.

LII

13. A method as in claim 11 which includes the added step of supplyingDC current to said cell to increase the rate of oxidation of said NH orNl-L generated by the action of urease on urea in hemodialysis fluid insaid electrochemical cell.

14. A method as in claim 11 which includes the added step of supplyingair or oxygen to the cathode portion of said cell.

15. A method as in claim 1 wherein said toxic substance is urea in ahemodialysis fluid.

16. A method as in claim 15 wherein said step of contacting includespassing the dialysate of said patient in hemodialysis through anextracorporeal shunt in which said electrochemical cell is disposed.

17. A method as in claim 15 which includes the added step of supplyingDC current to said cell to increase the rate of oxidation of said ureain the hemodialysis fluid in said electrochemical cell.

18. A method as in claim 15 wherein said electrochemical cell systemincludes a cathode assembly. and which method includes the added step ofsupplying air or oxygen to the cathode assembly of said cell.

19. A method as in claim 1 wherein said cell system includes ahydrophobic cathode assembly containing a high surface area metalconsisting essentially of platinum and an anode assembly containing ahigh surface area metal comprising platinum.

1. A method of treating patients having metabolic imbalances comprising the steps of: a. selecting a patient having relatively high concentrations of oxidizable toxic substances which their bodies are unable to metabolize or remove to substantially non-toxic levels, b. said toxic substances being present in extracellular fluid in at least one natural bodily fluid zone selected from the circulatory system, the pericardial sac, the abdominal peritoneum, the pleural cavity, and intratissue regions, c. surgically preparing said patient to provide said extracellular fluid from at least one of said natural bodily fluid zones, d. contacting said extracellular fluid with an electrochemical cell system adapted to oxidize said toxic substances to nontoxic or metabolizable substances, e. maintaining said contact for a time sufficient to reduce the amount of said substances to relatively non-toxic substances in said patient, and f. permitting said detoxified extracellular fluid to return to a physiologic environment in said patient.
 1. A method of treating patients having metabolic imbalances comprising the steps of: a. selecting a patient having relatively high concentrations of oxidizable toxic substances which their bodies are unable to metabolize or remove to substantially non-toxic levels, b. said toxic substances being present in extracellular fluid in at least one natural bodily fluid zone selected from the circulatory system, the pericardial sac, the abdominal peritoneum, the pleural cavity, and intratissue regions, c. surgically preparing said patient to provide said extracellular fluid from at least one of said natural bodily fluid zones, d. contacting said extracellular fluid with an electrochemical cell system adapted to oxidize said toxic substances to non-toxic or metabolizable substances, e. maintaining said contact for a time sufficient to reduce the amount of said substances to relatively non-toxic substances in said patient, and f. permitting said detoxified extracellular fluid to return to a physiologic environment in said patient.
 2. A method as in claim 1 wherein said toxic substances are selected from NH3, NH4 , urea, uric acid, digitalis glycosides, carbon monoxide, barbiturates, ketone bodies, aceto acetate, methanol, creatinine, alanine, ethanol, and mixtures thereof.
 3. A method of treating patients as in claim 2 wherein said toxic substances are selected from urea, uric acid, NH3, NH4 and mixtures thereof and said electrochemical cell system is adapted to oxidize said NH3 or NH4 to nontoxic N2 and H2O for a time sufficient to reduce said NH3 or NH4 to relatively safe levels.
 4. A method as in claim 1 wherein said step of contacting includes passing some of the blood of said Patient through an extracorporeal shunt in which said electrochemical cell is disposed.
 5. A method as in claim 3 which includes the added step of supplying DC current to said cell to increase the rate of oxidation of said toxic substances in said electrochemical cell.
 6. A method as in claim 3 wherein said electrochemical cell system includes a cathode assembly, and which method includes the added step of supplying air or oxygen to the cathode assembly of said cell.
 7. A method as in claim 3 wherein said cell is adapted for implantation and includes an oxygen permeable membrane in association with a cathode assembly, a membrane permeable to said toxic substances disposed in association with an anode assembly, and an ion transfer membrane between said assemblies, and said cell is disposed in said body so that said membranes are in contact with said extracellular fluid.
 8. A method as in claim 7 wherein said cell is implanted in a manner so that said anode membrane is exposed to blood of said patient.
 9. A method as in claim 3 which includes the steps of: a. Monitoring the output of said cell system as a measure of the patient''s toxic substance concentration, and b. Selectively supplying current to said cell when said monitored concentration reaches a predetermined level to promote oxidation of said substance.
 10. A method as in claim 1 wherein said cell system includes a hydrophobic cathode assembly containing a high surface area metal consisting essentially of silver and an anode assembly containing a high surface area metal comprising platinum.
 11. A method as in claim 2 wherein said toxic substances are NH3 and NH4 generated by the action of urease on dialized urea in a hemodialysis fluid.
 12. A method as in claim 11 wherein said step of contacting includes passing the dialysate of said patient through urease in a closed loop circuit in which said electrochemical cell is disposed downstream of said urease.
 13. A method as in claim 11 which includes the added step of supplying DC current to said cell to increase the rate of oxidation of said NH3 or NH4 generated by the action of urease on urea in hemodialysis fluid in said electrochemical cell.
 14. A method as in claim 11 which includes the added step of supplying air or oxygen to the cathode portion of said cell.
 15. A method as in claim 1 wherein said toxic substance is urea in a hemodialysis fluid.
 16. A method as in claim 15 wherein said step of contacting includes passing the dialysate of said patient in hemodialysis through an extracorporeal shunt in which said electrochemical cell is disposed.
 17. A method as in claim 15 which includes the added step of supplying DC current to said cell to increase the rate of oxidation of said urea in the hemodialysis fluid in said electrochemical cell.
 18. A method as in claim 15 wherein said electrochemical cell system includes a cathode assembly, and which method includes the added step of supplying air or oxygen to the cathode assembly of said cell. 